This is a proposal for funds to investigate the inhibition of retroviral replication through interference with the normal process of priming. The investigator suggests that this approach is a novel anti-retroviral approach and also provides a powerful tool for dissecting molecular aspects of priming. The proposal focuses on the molecular and virological mechanisms underlying inhibition of HIV-1 replication by mutant tRNAs. The investigator plans to pursue three specific objectives: First, he will elucidate the mechanism(s) by which mutant tRNA expression leads to marked suppression of HIV-1 replication and use this knowledge to design second generation tRNA mutants with enhanced ability to inhibit HIV-1 replication; second, he will analyze virus recovered from mutant tRNA-transduced cells for potential escape mechanisms; and third, he will examine the effect of mutant tRNA-based inhibition in combination with anti-viral drugs which target reverse transcription.